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879 results on '"Molenaar, Jan"'

151. The clinical and biological characteristics of NUP98-KDM5A pediatric acute myeloid leukemia

Author

Afd Pharmaceutics, Pharmaceutics, Noort, Sanne, Wander, Priscilla, Alonzo, Todd A, Smith, Jenny, Ries, Rhonda E, Gerbing, Robert B, Dolman, M Emmy M, Locatelli, Franco, Reinhardt, Dirk, Baruchel, Andre, Stary, Jan, Molenaar, Jan J, Stam, Ronald W, van den Heuvel-Eibrink, Marry M, Zwaan, Michel C, Meshinchi, Soheil, Afd Pharmaceutics, Pharmaceutics, Noort, Sanne, Wander, Priscilla, Alonzo, Todd A, Smith, Jenny, Ries, Rhonda E, Gerbing, Robert B, Dolman, M Emmy M, Locatelli, Franco, Reinhardt, Dirk, Baruchel, Andre, Stary, Jan, Molenaar, Jan J, Stam, Ronald W, van den Heuvel-Eibrink, Marry M, Zwaan, Michel C, and Meshinchi, Soheil

Published
2021

152. International Consensus on Minimum Preclinical Testing Requirements for the Development of Innovative Therapies For Children and Adolescents with Cancer

Author

Afd Pharmaceutics, Pharmaceutics, Vassal, Gilles, Houghton, Peter J, Pfister, Stefan M, Smith, Malcolm A, Caron, Huib N, Li, Xiao-Nan, Shields, David J, Witt, Olaf, Molenaar, Jan J, Colombetti, Sara, Schüler, Julia, Stancato, Lou F, Afd Pharmaceutics, Pharmaceutics, Vassal, Gilles, Houghton, Peter J, Pfister, Stefan M, Smith, Malcolm A, Caron, Huib N, Li, Xiao-Nan, Shields, David J, Witt, Olaf, Molenaar, Jan J, Colombetti, Sara, Schüler, Julia, and Stancato, Lou F

Published
2021

153. Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

Author

Afd Pharmaceutics, Pharmaceutics, van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, and Molenaar, Jan J

Published
2021

154. G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment

Author

Afd Pharmaceutics, Pharmaceutics, Martinez Sanz, Paula, van Rees, Dieke J, van Zogchel, Lieke M J, Klein, Bart, Bouti, Panagiota, Olsman, Hugo, Schornagel, Karin, Kok, Ivana, Sunak, Ali, Leeuwenburg, Kira, Timmerman, Ilse, Dierselhuis, Miranda P, Kholosy, Waleed M, Molenaar, Jan J, van Bruggen, Robin, van den Berg, Timo K, Kuijpers, Taco W, Matlung, Hanke L, Tytgat, Godelieve A M, Franke, Katka, Afd Pharmaceutics, Pharmaceutics, Martinez Sanz, Paula, van Rees, Dieke J, van Zogchel, Lieke M J, Klein, Bart, Bouti, Panagiota, Olsman, Hugo, Schornagel, Karin, Kok, Ivana, Sunak, Ali, Leeuwenburg, Kira, Timmerman, Ilse, Dierselhuis, Miranda P, Kholosy, Waleed M, Molenaar, Jan J, van Bruggen, Robin, van den Berg, Timo K, Kuijpers, Taco W, Matlung, Hanke L, Tytgat, Godelieve A M, and Franke, Katka

Published
2021

156. Neuroblastoma and DIPG Organoid Coculture System for Personalized Assessment of Novel Anticancer Immunotherapies

Author

Afd Pharmaceutics, Pharmaceutics, M Kholosy, Waleed, Derieppe, Marc, van den Ham, Femke, Ober, Kim, Su, Yan, Custers, Lars, Schild, Linda, M J van Zogchel, Lieke, M Wellens, Lianne, R Ariese, Hendrikus, Szanto, Celina L, Wienke, Judith, Dierselhuis, Miranda P, van Vuurden, Dannis, Dolman, Emmy M, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, M Kholosy, Waleed, Derieppe, Marc, van den Ham, Femke, Ober, Kim, Su, Yan, Custers, Lars, Schild, Linda, M J van Zogchel, Lieke, M Wellens, Lianne, R Ariese, Hendrikus, Szanto, Celina L, Wienke, Judith, Dierselhuis, Miranda P, van Vuurden, Dannis, Dolman, Emmy M, and Molenaar, Jan J

Published
2021

157. Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Author

Afd Pharmaceutics, Pharmaceutics, Calandrini, Camilla, van Hooff, Sander R, Paassen, Irene, Ayyildiz, Dilara, Derakhshan, Sepide, Dolman, M Emmy M, Langenberg, Karin P S, van de Ven, Marieke, de Heus, Cecilia, Liv, Nalan, Kool, Marcel, de Krijger, Ronald R, Tytgat, Godelieve A M, van den Heuvel-Eibrink, Marry M, Molenaar, Jan J, Drost, Jarno, Afd Pharmaceutics, Pharmaceutics, Calandrini, Camilla, van Hooff, Sander R, Paassen, Irene, Ayyildiz, Dilara, Derakhshan, Sepide, Dolman, M Emmy M, Langenberg, Karin P S, van de Ven, Marieke, de Heus, Cecilia, Liv, Nalan, Kool, Marcel, de Krijger, Ronald R, Tytgat, Godelieve A M, van den Heuvel-Eibrink, Marry M, Molenaar, Jan J, and Drost, Jarno

Published
2021

158. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Author

van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P. S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan-Henning, Fleischhack, Gudrun, Tippelt, Stephan, von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., von Bueren, Andre O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Woessmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Fruehwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Ora, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jaeger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T. W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., Witt, Olaf, van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P. S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan-Henning, Fleischhack, Gudrun, Tippelt, Stephan, von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., von Bueren, Andre O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Woessmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Fruehwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Ora, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jaeger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T. W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., and Witt, Olaf

Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.

Published
2021

159. The pediatric precision oncology inform registry:Clinical outcome and benefit for patients with very high-evidence targets

Author

Van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P.S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, Von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan Henning, Fleischhack, Gudrun, Tippelt, Stephan, Von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., Von Bueren, André O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Wößmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Frühwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Øra, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jäger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, Von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T.W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., Witt, Olaf, Van Tilburg, Cornelis M., Pfaff, Elke, Pajtler, Kristian W., Langenberg, Karin P.S., Fiesel, Petra, Jones, Barbara C., Balasubramanian, Gnana Prakash, Stark, Sebastian, Johann, Pascal D., Blattner-Johnson, Mirjam, Schramm, Kathrin, Dikow, Nicola, Hirsch, Steffen, Sutter, Christian, Grund, Kerstin, Von Stackelberg, Arend, Kulozik, Andreas E., Lissat, Andrej, Borkhardt, Arndt, Meisel, Roland, Reinhardt, Dirk, Klusmann, Jan Henning, Fleischhack, Gudrun, Tippelt, Stephan, Von Schweinitz, Dietrich, Schmid, Irene, Kramm, Christof M., Von Bueren, André O., Calaminus, Gabriele, Vorwerk, Peter, Graf, Norbert, Westermann, Frank, Fischer, Matthias, Eggert, Angelika, Burkhardt, Birgit, Wößmann, Wilhelm, Nathrath, Michaela, Hecker-Nolting, Stefanie, Frühwald, Michael C., Schneider, Dominik T., Brecht, Ines B., Ketteler, Petra, Fulda, Simone, Koscielniak, Ewa, Meister, Michael T., Scheer, Monika, Hettmer, Simone, Schwab, Matthias, Tremmel, Roman, Øra, Ingrid, Hutter, Caroline, Gerber, Nicolas U., Lohi, Olli, Kazanowska, Bernarda, Kattamis, Antonis, Filippidou, Maria, Goemans, Bianca, Zwaan, C. Michel, Milde, Till, Jäger, Natalie, Wolf, Stephan, Reuss, David, Sahm, Felix, Von Deimling, Andreas, Dirksen, Uta, Freitag, Angelika, Witt, Ruth, Lichter, Peter, Kopp-Schneider, Annette, Jones, David T.W., Molenaar, Jan J., Capper, David, Pfister, Stefan M., and Witt, Olaf

Abstract

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.

Published
2021

160. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Author

Groep Holstege, CTI Leusen, CMM Groep Burgering, Cancer, Zorgeenheid Kinderchirurgie Medisch, Onderzoek Beeld, Pathologie Pathologen staf, Kildisiute, Gerda, Kholosy, Waleed M., Young, Matthew D., Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R., Pacyna, Clarissa N., Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M., Langenberg-Ververgaert, Karin P.S., Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C.P., Tas, Michelle L., Wijnen, Marc H.W.A., van Noesel, Max M., del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C., Haniffa, Muzlifah, Teichmann, Sarah A., Rampling, Dyanne, Sebire, Neil J., He, Xiaoling, de Krijger, Ronald R., Barker, Roger A., Meyer, Kerstin B., Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J., Behjati, Sam, Groep Holstege, CTI Leusen, CMM Groep Burgering, Cancer, Zorgeenheid Kinderchirurgie Medisch, Onderzoek Beeld, Pathologie Pathologen staf, Kildisiute, Gerda, Kholosy, Waleed M., Young, Matthew D., Roberts, Kenny, Elmentaite, Rasa, van Hooff, Sander R., Pacyna, Clarissa N., Khabirova, Eleonora, Piapi, Alice, Thevanesan, Christine, Bugallo-Blanco, Eva, Burke, Christina, Mamanova, Lira, Keller, Kaylee M., Langenberg-Ververgaert, Karin P.S., Lijnzaad, Philip, Margaritis, Thanasis, Holstege, Frank C.P., Tas, Michelle L., Wijnen, Marc H.W.A., van Noesel, Max M., del Valle, Ignacio, Barone, Giuseppe, van der Linden, Reinier, Duncan, Catriona, Anderson, John, Achermann, John C., Haniffa, Muzlifah, Teichmann, Sarah A., Rampling, Dyanne, Sebire, Neil J., He, Xiaoling, de Krijger, Ronald R., Barker, Roger A., Meyer, Kerstin B., Bayraktar, Omer, Straathof, Karin, Molenaar, Jan J., and Behjati, Sam

Published
2021

161. Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Author

Groep Holstege, CMM Groep Klumperman, Cancer, CMM Sectie Celbiologie, CMM groep Liv, Pathologie Pathologen staf, Speerpunt, Zorg en O&O, Child Health, Calandrini, Camilla, van Hooff, Sander R., Paassen, Irene, Ayyildiz, Dilara, Derakhshan, Sepide, Dolman, M. Emmy M., Langenberg, Karin P.S., van de Ven, Marieke, de Heus, Cecilia, Liv, Nalan, Kool, Marcel, de Krijger, Ronald R., Tytgat, Godelieve A.M., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., Drost, Jarno, Groep Holstege, CMM Groep Klumperman, Cancer, CMM Sectie Celbiologie, CMM groep Liv, Pathologie Pathologen staf, Speerpunt, Zorg en O&O, Child Health, Calandrini, Camilla, van Hooff, Sander R., Paassen, Irene, Ayyildiz, Dilara, Derakhshan, Sepide, Dolman, M. Emmy M., Langenberg, Karin P.S., van de Ven, Marieke, de Heus, Cecilia, Liv, Nalan, Kool, Marcel, de Krijger, Ronald R., Tytgat, Godelieve A.M., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., and Drost, Jarno

Published
2021

162. The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Author

CTI Van Wijk, Arts-assistenten Kinderen, CDL Patiëntenzorg MI, CTI Research, Infection & Immunity, Cancer, Wienke, Judith, Dierselhuis, Miranda P, Tytgat, Godelieve A M, Künkele, Annette, Nierkens, Stefan, Molenaar, Jan J, CTI Van Wijk, Arts-assistenten Kinderen, CDL Patiëntenzorg MI, CTI Research, Infection & Immunity, Cancer, Wienke, Judith, Dierselhuis, Miranda P, Tytgat, Godelieve A M, Künkele, Annette, Nierkens, Stefan, and Molenaar, Jan J

Published
2021

163. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Author

Molenaar, Jan J., Koster, Jan, Zwijnenburg, Danny A., van Sluis, Peter, Valentijn, Linda J., van der Ploeg, Ida, Hamdi, Mohamed, van Nes, Johan, Westerman, Bart A., van Arkel, Jennemiek, Ebus, Marli E., Haneveld, Franciska, Lakeman, Arjan, Schild, Linda, Molenaar, Piet, Stroeken, Peter, van Noesel, Max M., Ora, Ingrid, Santo, Evan E., Caron, Huib N., Westerhout, Ellen M., and Versteeg, Rogier

Subjects
Nucleotide sequencing -- Usage, Immunohistochemistry -- Usage, DNA sequencing -- Usage, Neuroblastoma -- Risk factors -- Genetic aspects -- Prognosis -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour (1). Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%) (2-5).Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma (6). These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization (7-9).Inaddition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCNamplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours., Neuroblastoma have a highly variable clinical outcome, with an excellent prognosis for stage 1 and 2 tumours, but a poor outcome for high-stage tumours. Stage 4S neuroblastoma are metastasized but [...]

Published
2012
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164. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity

Author

Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L, Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H D, Visser, Lindy L, Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A M, Kemmeren, Patrick, de Krijger, Ronald R, Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C, van den Heuvel-Eibrink, Marry M, Molenaar, Jan J, van Boxtel, Ruben, Holstege, Frank C P, Clevers, Hans, Drost, Jarno, UU BETA RESEARCH, Faculteit Diergeneeskunde, Paediatric Oncology, CCA - Cancer Treatment and Quality of Life, Hubrecht Institute for Developmental Biology and Stem Cell Research, UU BETA RESEARCH, and Faculteit Diergeneeskunde

Subjects
0301 basic medicine, Male, Pathology, Renal Cell/drug therapy, Genotyping Techniques, Cell Culture Techniques, General Physics and Astronomy, Cell Culture Techniques/methods, Nephroma, Mesoblastic/drug therapy, Stem cells, Kidney, Drug Screening Assays, 0302 clinical medicine, Kidney/pathology, Tumor Cells, Cultured, RNA-Seq, Precision Medicine, lcsh:Science, Child, Rhabdoid Tumor/drug therapy, Cancer, Biological Specimen Banks, Netherlands, Adult stem cells, Cultured, Multidisciplinary, Precision Medicine/methods, Biobank, Kidney Neoplasms, Tumor Cells, 3. Good health, Organoids, Gene Expression Regulation, Neoplastic, Mesoblastic/drug therapy, Kidney Neoplasms/drug therapy, 030220 oncology & carcinogenesis, Child, Preschool, Female, Single-Cell Analysis, medicine.medical_specialty, Stromal cell, Adolescent, Science, Antitumor/methods, Drug Screening Assays, Antitumor/methods, Transfection, Wilms Tumor, Article, General Biochemistry, Genetics and Molecular Biology, Paediatric cancer, 03 medical and health sciences, Genetic Heterogeneity, Young Adult, medicine, Organoid, Carcinoma, Humans, Nephroma, Kidney tumour, Nephroma, Mesoblastic, Cancer models, Preschool, Carcinoma, Renal Cell, Rhabdoid Tumor, Neoplastic, Whole Genome Sequencing, Genetic heterogeneity, business.industry, Infant, General Chemistry, DNA Methylation, medicine.disease, Organoids/pathology, 030104 developmental biology, Gene Expression Regulation, Carcinoma, Renal Cell/drug therapy, Wilms Tumor/drug therapy, lcsh:Q, Drug Screening Assays, Antitumor, business, Kidney cancer
Abstract

Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine., Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.

Published
2020

166. High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells

Author

Vernooij, Lindy, primary, Bate-Eya, Laurel T., additional, Alles, Lindy K., additional, Lee, Jasmine Y., additional, Koopmans, Bianca, additional, Jonus, Hunter C., additional, Schubert, Nil A., additional, Schild, Linda, additional, Lelieveld, Daphne, additional, Egan, David A., additional, Kerstjens, Mark, additional, Stam, Ronald W., additional, Koster, Jan, additional, Goldsmith, Kelly C., additional, Molenaar, Jan J., additional, and Dolman, M. Emmy M., additional

Published
2021
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168. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Author

Kildisiute, Gerda, primary, Kholosy, Waleed M., additional, Young, Matthew D., additional, Roberts, Kenny, additional, Elmentaite, Rasa, additional, van Hooff, Sander R., additional, Pacyna, Clarissa N., additional, Khabirova, Eleonora, additional, Piapi, Alice, additional, Thevanesan, Christine, additional, Bugallo-Blanco, Eva, additional, Burke, Christina, additional, Mamanova, Lira, additional, Keller, Kaylee M., additional, Langenberg-Ververgaert, Karin P.S., additional, Lijnzaad, Philip, additional, Margaritis, Thanasis, additional, Holstege, Frank C.P., additional, Tas, Michelle L., additional, Wijnen, Marc H.W.A., additional, van Noesel, Max M., additional, del Valle, Ignacio, additional, Barone, Giuseppe, additional, van der Linden, Reinier, additional, Duncan, Catriona, additional, Anderson, John, additional, Achermann, John C., additional, Haniffa, Muzlifah, additional, Teichmann, Sarah A., additional, Rampling, Dyanne, additional, Sebire, Neil J., additional, He, Xiaoling, additional, de Krijger, Ronald R., additional, Barker, Roger A., additional, Meyer, Kerstin B., additional, Bayraktar, Omer, additional, Straathof, Karin, additional, Molenaar, Jan J., additional, and Behjati, Sam, additional

Published
2021
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170. Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

Author

Wellens, Lianne M, Deken, Marion M, Sier, Cornelis F M, Johnson, Hannah R, de la Jara Ortiz, Fàtima, Bhairosingh, Shadhvi S, Houvast, Ruben D, Kholosy, Waleed M, Baart, Victor M, Pieters, Annique M M J, de Krijger, Ronald R, Molenaar, Jan J, Wehrens, Ellen J, Dekkers, Johanna F, Wijnen, Marc H W A, Vahrmeijer, Alexander L, Rios, Anne C, UU BETA RESEARCH, and UU BETA RESEARCH

Subjects
Fluorescence-lifetime imaging microscopy, Indoles, medicine.medical_treatment, Nude, lcsh:Medicine, Neuroblastoma, Mice, 0302 clinical medicine, Gangliosides, Neoplasms, Pediatric surgery, Benzenesulfonates/therapeutic use, lcsh:Science, 0303 health sciences, Tumor, Multidisciplinary, medicine.diagnostic_test, Brain Neoplasms, Benzenesulfonates, Flow Cytometry, 3. Good health, Surgical oncology, 030220 oncology & carcinogenesis, Female, Indoles/therapeutic use, medicine.medical_specialty, Neuroblastoma/metabolism, Mice, Nude, Gangliosides/metabolism, Article, Cell Line, Fluorescent Dyes/therapeutic use, Flow cytometry, Paediatric cancer, Experimental, 03 medical and health sciences, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Cancer models, Fluorescent Dyes, 030304 developmental biology, business.industry, lcsh:R, Neoplasms, Experimental, Immunotherapy, Translational research, medicine.disease, In vitro, Surgery, Tissue Array Analysis, Cell culture, lcsh:Q, business, Neoplasm Transplantation, Brain Neoplasms/metabolism
Abstract

Neuroblastoma resection represents a major challenge in pediatric surgery, because of the high risk of complications. Fluorescence-guided surgery (FGS) could lower this risk by facilitating discrimination of tumor from normal tissue and is gaining momentum in adult oncology. Here, we provide the first molecular-targeted fluorescent agent for FGS in pediatric oncology, by developing and preclinically evaluating a GD2-specific tracer consisting of the immunotherapeutic antibody dinutuximab-beta, recently approved for neuroblastoma treatment, conjugated to near-infrared (NIR) fluorescent dye IRDye800CW. We demonstrated specific binding of anti-GD2-IRDye800CW to human neuroblastoma cells in vitro and in vivo using xenograft mouse models. Furthermore, we defined an optimal dose of 1 nmol, an imaging time window of 4 days after administration and show that neoadjuvant treatment with anti-GD2 immunotherapy does not interfere with fluorescence imaging. Importantly, as we observed universal, yet heterogeneous expression of GD2 on neuroblastoma tissue of a wide range of patients, we implemented a xenograft model of patient-derived neuroblastoma organoids with differential GD2 expression and show that even low GD2 expressing tumors still provide an adequate real-time fluorescence signal. Hence, the imaging advancement presented in this study offers an opportunity for improving surgery and potentially survival of a broad group of children with neuroblastoma.

Published
2020

171. Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

Author

Manzella, Gabriele, Schreck, Leonie D, Breunis, Willemijn B, Molenaar, Jan, Merks, Hans, Barr, Frederic G, Sun, Wenyue, Römmele, Michaela, Zhang, Luduo, Tchinda, Joelle, Ngo, Quy A, Bode, Peter, Delattre, Olivier, Surdez, Didier, Rekhi, Bharat, Niggli, Felix K, Schäfer, Beat W, Wachtel, Marco, University of Zurich, Schäfer, Beat W, University Children’s Hospital Zurich, Princess Máxima Center for Pediatric Oncology [Utrecht, Pays-Bas], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University hospital of Zurich [Zurich], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Tata Memorial Centre, The work was supported by grants from the Swiss National Science Foundation (3100-156923 and 3100-175558), the Clinical Research Priority Program (CCRP) 'Precision Heamatology/Oncology' and the Childhood Cancer Research Foundation Switzerland to BS. Concerning samples originating from PARIS, the PDX development was supported by the Société Française de Lutte contre les Cancers et les Leucémies de l’Enfant et l’Adolescent (Fondation Enfants et Santé), la Ligue Nationale Contre le Cancer, the Fondation AREMIG, and the Association Thibault BRIET, la Ligue Nationale Contre le Cancer and by the following grants: ERA-NET TRANSCAN JTC 2014 (TRAN201501238), TRANSCAN JTC 2017 (TRANS201801292) and H2020-lMI2-JTl-201 5-07 (116064 – ITCC P4). The MAPPYACTS protocol is supported by the Institut National du Cancer grant PHRCK14–175, the Fondation ARC grant MAPY201501241 and Imagine For Margo., UU BETA RESEARCH, Princess Máxima Center for Pediatric Oncology, and Bodescot, Myriam

Subjects
Science, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, 1600 General Chemistry, Drug Screening Assays, Antitumor/methods, Article, Paediatric cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, 1300 General Biochemistry, Genetics and Molecular Biology, Rhabdomyosarcoma, Tumor Cells, Cultured, Animals, Humans, Cancer models, lcsh:Science, Protein Kinase Inhibitors, Biological Specimen Banks, Gene Expression Profiling, Xenograft Model Antitumor Assays, 3100 General Physics and Astronomy, Phenotype, Rhabdomyosarcoma/drug therapy, 10036 Medical Clinic, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Tumor Cells, Cultured/drug effects, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:Q, Drug Screening Assays, Antitumor, Proto-Oncogene Proteins c-akt/antagonists & inhibitors, Proto-Oncogene Proteins c-akt, Antineoplastic Agents/pharmacology
Abstract

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting., Patient-specific precision medicine approaches are important for future cancer therapies. Here, the authors show that functional drug profiling with Rhabdomyosarcoma cells isolated from PDX and primary patient tumors uncovers patient-specific vulnerabilities.

Published
2020

172. Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Author

Schubert, Nil A, Schild, Linda, van Oirschot, Stijn, Keller, Kaylee M, Alles, Lindy K, Vernooij, Lindy, Nulle, Marloes E, Dolman, M Emmy M, van den Boogaard, Marlinde L, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
0301 basic medicine, Cancer Research, CDK4, Idasanutlin, CDK4/6 inhibitor, Paediatric cancer, 03 medical and health sciences, chemistry.chemical_compound, CDKN2A, Mice, Neuroblastoma, 0302 clinical medicine, Cyclin D1, p14arf, MDM2, medicine, Animals, Humans, IDASANUTLIN, Precision Medicine, Abemaciclib, neoplasms, biology, Precision medicine, medicine.disease, 030104 developmental biology, chemistry, Oncology, Cell culture, MDM2 inhibitor, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Mdm2, Tumor Suppressor Protein p53
Abstract

Background Despite intensive treatment protocols and recent advances, neuroblastomas still account for approximately 15% of all childhood cancer deaths. In contrast with adult cancers, p53 pathway inactivation in neuroblastomas is rarely caused by p53 mutation but rather by altered MDM2 or p14ARF expression. Moreover, neuroblastomas are characterised by high proliferation rates, frequently triggered by pRb pathway dysfunction due to aberrant expression of cyclin D1, CDK4 or p16INK4a. Simultaneous disturbance of these pathways can occur via co-amplification of MDM2 and CDK4 or homozygous deletion of CDKN2A, which encodes both p14ARF and p16INK4a. Methods and results We examined whether both single and combined inhibition of MDM2 and CDK4/6 is effective in reducing neuroblastoma cell viability. In our panel of ten cell lines with a spectrum of aberrations in the p53 and pRb pathway, idasanutlin and abemaciclib were the most potent MDM2 and CDK4/6 inhibitors, respectively. No correlation was observed between the genetic background and response to the single inhibitors. We confirmed this lack of correlation in isogenic systems overexpressing MDM2 and/or CDK4. In addition, combined inhibition did not result in synergistic effects. Instead, abemaciclib diminished the pro-apoptotic effect of idasanutlin, leading to slightly antagonistic effects. In vivo treatment with idasanutlin and abemaciclib led to reduced tumour growth compared with single drug treatment, but no synergistic response was observed. Conclusion We conclude that p53 and pRb pathway aberrations cannot be used as predictive biomarkers for neuroblastoma sensitivity to MDM2 and/or CDK4/6 inhibitors. Moreover, we advise to be cautious with combining these inhibitors in neuroblastomas.

Published
2020

173. The landscape of genomic alterations across childhood cancers

Author

Gröbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Lichter, Peter, Weber, Ursula, Eils, Roland, Korshunov, Andrey, Witt, Olaf, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jörg, von Kalle, Christof, Schmidt, Manfred, Bartholomä, Cynthia, Taylor, Michael, Jones, David, Jäger, Natalie, Korbel, Jan, Stütz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jörg, Landgraf, Pablo, Brors, Benedikt, Zapatka, Marc, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Burkhardt, Birgit, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Löffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trümper, Lorenz, Zenz, Thorsten, Kube, Dieter, Küppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Möller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, López, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Schlesner, Matthias, Stadler, Peter F., Sungalee, Stephanie, Kratz, Christian P., van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Jones, David T. W., Chavez, Lukas, Pfister, Stefan M., Other departments, CCA - Cancer biology and immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Oncogenomics

Subjects
0301 basic medicine, Adult, Mutation rate, Mutation/genetics, Adolescent, DNA Copy Number Variations, Medizin, Biology, DNA Copy Number Variations/genetics, Germ-Line Mutation/genetics, Germline, Cohort Studies, 03 medical and health sciences, Young Adult, Germline mutation, Neoplasms/classification, Mutation Rate, Neoplasms, medicine, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy, ddc:610, Mutation frequency, Child, Germ-Line Mutation, Genetics, Chromothripsis, Multidisciplinary, Genome, Human, Genetic Predisposition to Disease/genetics, Cancer, Genomics, medicine.disease, Diploidy, Human genetics, 3. Good health, ddc, 030104 developmental biology, Mutation (genetic algorithm), Mutation, Genome, Human/genetics, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53
Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

Published
2020

174. Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma

Author

Moreno, Lucas, Barone, Giuseppe, DuBois, Steven G, Molenaar, Jan, Fischer, Matthias, Schulte, Johannes, Eggert, Angelika, Schleiermacher, Gudrun, Speleman, Frank, Chesler, Louis, Geoerger, Birgit, Hogarty, Michael D, Irwin, Meredith S, Bird, Nick, Blanchard, Guy B, Buckland, Sean, Caron, Hubert, Davis, Susan, De Wilde, Bram, Deubzer, Hedwig E, Dolman, Emmy, Eilers, Martin, George, Rani E, George, Sally, Jaroslav, Štěrba, Maris, John M, Marshall, Lynley, Merchant, Melinda, Mortimer, Peter, Owens, Cormac, Philpott, Anna, Poon, Evon, Shay, Jerry W, Tonelli, Roberto, Valteau-Couanet, Dominique, Vassal, Gilles, Park, Julie R, Pearson, Andrew D J, UU BETA RESEARCH, Blanchard, Guy [0000-0002-3689-0522], Philpott, Anna [0000-0003-3789-2463], Apollo - University of Cambridge Repository, UU BETA RESEARCH, Moreno L., Barone G., DuBois S.G., Molenaar J., Fischer M., Schulte J., Eggert A., Schleiermacher G., Speleman F., Chesler L., Geoerger B., Hogarty M.D., Irwin M.S., Bird N., Blanchard G.B., Buckland S., Caron H., Davis S., De Wilde B., Deubzer H.E., Dolman E., Eilers M., George R.E., George S., Jaroslav, Maris J.M., Marshall L., Merchant M., Mortimer P., Owens C., Philpott A., Poon E., Shay J.W., Tonelli R., Valteau-Couanet D., Vassal G., Park J.R., and Pearson A.D.J.

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Drug development, Antineoplastic Agents, Medical Oncology, Pediatrics, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, Clinical trials, Phase I, Drug Development, Internal medicine, MYCN, Drug Discovery, medicine, Anaplastic lymphoma kinase, Humans, Molecular Targeted Therapy, Child, Protein Kinase Inhibitors, ATRX, Drug discovery, business.industry, Paediatric oncology, Brain Neoplasms, Therapies, Investigational, Epigenetic, Cancer, Preclinical testing, Congresses as Topic, medicine.disease, 3. Good health, Clinical trial, Europe, 030104 developmental biology, 030220 oncology & carcinogenesis, Epigenetics, business
Abstract

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. (C) 2020 Elsevier Ltd. All rights reserved.

Published
2020

175. Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers

Author

Schubert, Nil A, Lowery, Caitlin D, Bergthold, Guillaume, Koster, Jan, Eleveld, Thomas F, Rodríguez, Ana, Jones, David T W, Vassal, Gilles, Stancato, Louis F, Pfister, Stefan M, Caron, Hubert N, Molenaar, Jan J, UU BETA RESEARCH, Oncogenomics, CCA - Cancer biology and immunology, Graduate School, and UU BETA RESEARCH

Subjects
Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Adolescent, Disease, Scientific literature, Pediatrics, Proof of Concept Study, Article, 03 medical and health sciences, 0302 clinical medicine, Paediatric cancer, Neoplasms, medicine, Humans, Child, Preschool, Intensive care medicine, Repurposing, Paediatric oncology, business.industry, Cancer, medicine.disease, Clinical development, 3. Good health, Critical appraisal, 030104 developmental biology, Oncology, Drug development, Preclinical research, Proof of concept, Child, Preschool, 030220 oncology & carcinogenesis, Systematic review, Female, Targeted drugs, business, Neoplasms/epidemiology
Abstract

Background Children with cancer are in urgent need of new therapies, as approximately 25% of patients experience a relapse and 20% succumb to their disease. Moreover, the majority of survivors suffer from clinically relevant health problems. Repurposing of targeted agents developed for adult indications could provide novel therapeutic options for paediatric cancer patients. To prioritise targeted drugs for paediatric clinical development, we applied a systematic review methodology to develop a Target Actionability Review (TAR) strategy. These TARs assess the strength and completeness of published preclinical proof-of-concept (PoC) data by structured critical appraisal of and summarising the available scientific literature for a specific target (pathway) and the associated drugs in paediatric tumours. Methods A sensitive literature search in PubMed was performed and relevant papers were identified. For each paper, the individual experimental findings were extracted, marked for paediatric tumour type and categorised into nine separate PoC data modules. Each experimental finding was scored for experimental outcome and quality independently by two reviewers; discrepancies were assessed by a third reviewer and resolved by adjudication. Scores corresponding to one PoC module were merged for each tumour type and visualised in a heat map matrix in the publicly available R2 data portal [r2.amc.nl]. Results and conclusions To test our TAR methodology, we conducted a pilot study on MDM2 and TP53. The heat map generated from analysis of 161 publications provides a rationale to support drug development in specific paediatric solid and brain tumour types. Furthermore, our review highlights tumour types where preclinical data are incomplete or lacking and for which additional preclinical testing is advisable., Highlights • A new strategy to review literature on targeted compounds in paediatric cancer. • Results help to guide and prioritise clinical development of novel targeted agents. • Outcomes are visualised in a publicly available, interactive heat map. • We applied this unique methodology to MDM2 and TP53 and MDM2 inhibitors.

Published
2020
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176. PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

Author

Milosevic, Jelena, Fransson, Susanne, Gulyas, Miklos, Gallo-Oller, Gabriel, Olsen, Thale K, Treis, Diana, Wickström, Malin, Elfman, Lotta HM, Sveinbjornsson, Baldur, Hertwig, Falk, Bartenhagen, Christoph, Reinsbach, Susanne, Wilhelm, Margareta, Abel, Frida, Javanmardi, Niloufar, Thankaswamy-Kosalai, Subazini, Eissler, Nina, Kock, Anna, Shi, Yao, Tanino, Keiji, Hehir-Kwa, Jane Y, Mensenkamp, Arjen, Tytgat, Godelieve AM, Kanduri, Chandrasekhar, Holmberg, Johan, Gisselsson, David, Molenaar, Jan J, Jongmans, Marjolijn, Fischer, Matthias, Kool, Marcel, Sakaguchi, Kazuyasu, Baryawno, Ninib, Martinsson, Tommy, Johnsen, John Inge, Kogner, Per, Milosevic, Jelena, Fransson, Susanne, Gulyas, Miklos, Gallo-Oller, Gabriel, Olsen, Thale K, Treis, Diana, Wickström, Malin, Elfman, Lotta HM, Sveinbjornsson, Baldur, Hertwig, Falk, Bartenhagen, Christoph, Reinsbach, Susanne, Wilhelm, Margareta, Abel, Frida, Javanmardi, Niloufar, Thankaswamy-Kosalai, Subazini, Eissler, Nina, Kock, Anna, Shi, Yao, Tanino, Keiji, Hehir-Kwa, Jane Y, Mensenkamp, Arjen, Tytgat, Godelieve AM, Kanduri, Chandrasekhar, Holmberg, Johan, Gisselsson, David, Molenaar, Jan J, Jongmans, Marjolijn, Fischer, Matthias, Kool, Marcel, Sakaguchi, Kazuyasu, Baryawno, Ninib, Martinsson, Tommy, Johnsen, John Inge, and Kogner, Per

Abstract

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors., Senior authors with equal contribution: John Inge Johnsen and Per Kogner

Published
2020
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177. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Author

UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, Chesler, Louis, UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, and Chesler, Louis

Published
2020

178. Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

Author

UU BETA RESEARCH, George, Sally L, Lorenzi, Federica, King, David, Hartlieb, Sabine, Campbell, James, Pemberton, Helen, Toprak, Umut H, Barker, Karen, Tall, Jennifer, da Costa, Barbara Martins, van den Boogaard, Marlinde L, Dolman, M Emmy M, Molenaar, Jan J, Bryant, Helen E, Westermann, Frank, Lord, Christopher J, Chesler, Louis, UU BETA RESEARCH, George, Sally L, Lorenzi, Federica, King, David, Hartlieb, Sabine, Campbell, James, Pemberton, Helen, Toprak, Umut H, Barker, Karen, Tall, Jennifer, da Costa, Barbara Martins, van den Boogaard, Marlinde L, Dolman, M Emmy M, Molenaar, Jan J, Bryant, Helen E, Westermann, Frank, Lord, Christopher J, and Chesler, Louis

Published
2020

179. Neuroblastoma stage 4S: Tumor regression rate and risk factors of progressive disease

Author

UU BETA RESEARCH, Tas, Michelle L, Nagtegaal, Michelle, Kraal, Kathelijne C J M, Tytgat, Godelieve A M, Abeling, Nico G G M, Koster, Jan, Pluijm, Saskia M F, Zwaan, C Michel, de Keizer, Bart, Molenaar, Jan J, van Noesel, Max M, UU BETA RESEARCH, Tas, Michelle L, Nagtegaal, Michelle, Kraal, Kathelijne C J M, Tytgat, Godelieve A M, Abeling, Nico G G M, Koster, Jan, Pluijm, Saskia M F, Zwaan, C Michel, de Keizer, Bart, Molenaar, Jan J, and van Noesel, Max M

Published
2020

180. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity

Author

UU BETA RESEARCH, Faculteit Diergeneeskunde, Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L, Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H D, Visser, Lindy L, Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A M, Kemmeren, Patrick, de Krijger, Ronald R, Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C, van den Heuvel-Eibrink, Marry M, Molenaar, Jan J, van Boxtel, Ruben, Holstege, Frank C P, Clevers, Hans, Drost, Jarno, UU BETA RESEARCH, Faculteit Diergeneeskunde, Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L, Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H D, Visser, Lindy L, Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A M, Kemmeren, Patrick, de Krijger, Ronald R, Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C, van den Heuvel-Eibrink, Marry M, Molenaar, Jan J, van Boxtel, Ruben, Holstege, Frank C P, Clevers, Hans, and Drost, Jarno

Published
2020

181. Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma

Author

UU BETA RESEARCH, Moreno, Lucas, Barone, Giuseppe, DuBois, Steven G, Molenaar, Jan, Fischer, Matthias, Schulte, Johannes, Eggert, Angelika, Schleiermacher, Gudrun, Speleman, Frank, Chesler, Louis, Geoerger, Birgit, Hogarty, Michael D, Irwin, Meredith S, Bird, Nick, Blanchard, Guy B, Buckland, Sean, Caron, Hubert, Davis, Susan, De Wilde, Bram, Deubzer, Hedwig E, Dolman, Emmy, Eilers, Martin, George, Rani E, George, Sally, Jaroslav, Štěrba, Maris, John M, Marshall, Lynley, Merchant, Melinda, Mortimer, Peter, Owens, Cormac, Philpott, Anna, Poon, Evon, Shay, Jerry W, Tonelli, Roberto, Valteau-Couanet, Dominique, Vassal, Gilles, Park, Julie R, Pearson, Andrew D J, UU BETA RESEARCH, Moreno, Lucas, Barone, Giuseppe, DuBois, Steven G, Molenaar, Jan, Fischer, Matthias, Schulte, Johannes, Eggert, Angelika, Schleiermacher, Gudrun, Speleman, Frank, Chesler, Louis, Geoerger, Birgit, Hogarty, Michael D, Irwin, Meredith S, Bird, Nick, Blanchard, Guy B, Buckland, Sean, Caron, Hubert, Davis, Susan, De Wilde, Bram, Deubzer, Hedwig E, Dolman, Emmy, Eilers, Martin, George, Rani E, George, Sally, Jaroslav, Štěrba, Maris, John M, Marshall, Lynley, Merchant, Melinda, Mortimer, Peter, Owens, Cormac, Philpott, Anna, Poon, Evon, Shay, Jerry W, Tonelli, Roberto, Valteau-Couanet, Dominique, Vassal, Gilles, Park, Julie R, and Pearson, Andrew D J

Published
2020

182. Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

Author

UU BETA RESEARCH, Manzella, Gabriele, Schreck, Leonie D, Breunis, Willemijn B, Molenaar, Jan, Merks, Hans, Barr, Frederic G, Sun, Wenyue, Römmele, Michaela, Zhang, Luduo, Tchinda, Joelle, Ngo, Quy A, Bode, Peter, Delattre, Olivier, Surdez, Didier, Rekhi, Bharat, Niggli, Felix K, Schäfer, Beat W, Wachtel, Marco, UU BETA RESEARCH, Manzella, Gabriele, Schreck, Leonie D, Breunis, Willemijn B, Molenaar, Jan, Merks, Hans, Barr, Frederic G, Sun, Wenyue, Römmele, Michaela, Zhang, Luduo, Tchinda, Joelle, Ngo, Quy A, Bode, Peter, Delattre, Olivier, Surdez, Didier, Rekhi, Bharat, Niggli, Felix K, Schäfer, Beat W, and Wachtel, Marco

Published
2020

183. Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

Author

UU BETA RESEARCH, Wellens, Lianne M, Deken, Marion M, Sier, Cornelis F M, Johnson, Hannah R, de la Jara Ortiz, Fàtima, Bhairosingh, Shadhvi S, Houvast, Ruben D, Kholosy, Waleed M, Baart, Victor M, Pieters, Annique M M J, de Krijger, Ronald R, Molenaar, Jan J, Wehrens, Ellen J, Dekkers, Johanna F, Wijnen, Marc H W A, Vahrmeijer, Alexander L, Rios, Anne C, UU BETA RESEARCH, Wellens, Lianne M, Deken, Marion M, Sier, Cornelis F M, Johnson, Hannah R, de la Jara Ortiz, Fàtima, Bhairosingh, Shadhvi S, Houvast, Ruben D, Kholosy, Waleed M, Baart, Victor M, Pieters, Annique M M J, de Krijger, Ronald R, Molenaar, Jan J, Wehrens, Ellen J, Dekkers, Johanna F, Wijnen, Marc H W A, Vahrmeijer, Alexander L, and Rios, Anne C

Published
2020

184. Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers

Author

UU BETA RESEARCH, Schubert, Nil A, Lowery, Caitlin D, Bergthold, Guillaume, Koster, Jan, Eleveld, Thomas F, Rodríguez, Ana, Jones, David T W, Vassal, Gilles, Stancato, Louis F, Pfister, Stefan M, Caron, Hubert N, Molenaar, Jan J, UU BETA RESEARCH, Schubert, Nil A, Lowery, Caitlin D, Bergthold, Guillaume, Koster, Jan, Eleveld, Thomas F, Rodríguez, Ana, Jones, David T W, Vassal, Gilles, Stancato, Louis F, Pfister, Stefan M, Caron, Hubert N, and Molenaar, Jan J

Published
2020

186. Neuroblastoma stage 4S: Tumor regression rate and risk factors of progressive disease

Author

MS Radiologie, Cancer, Tas, Michelle L., Nagtegaal, Michelle, Kraal, Kathelijne C.J.M., Tytgat, Godelieve A.M., Abeling, Nico G.G.M., Koster, Jan, Pluijm, Saskia M.F., Zwaan, C. Michel, de Keizer, Bart, Molenaar, Jan J., van Noesel, Max M., MS Radiologie, Cancer, Tas, Michelle L., Nagtegaal, Michelle, Kraal, Kathelijne C.J.M., Tytgat, Godelieve A.M., Abeling, Nico G.G.M., Koster, Jan, Pluijm, Saskia M.F., Zwaan, C. Michel, de Keizer, Bart, Molenaar, Jan J., and van Noesel, Max M.

Published
2020

187. Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

Author

Hubrecht Institute with UMC, Wellens, Lianne M., Deken, Marion M., Sier, Cornelis F.M., Johnson, Hannah R., de la Jara Ortiz, Fàtima, Bhairosingh, Shadhvi S., Houvast, Ruben D., Kholosy, Waleed M., Baart, Victor M., Pieters, Annique M.M.J., de Krijger, Ronald R., Molenaar, Jan J., Wehrens, Ellen J., Dekkers, Johanna F., Wijnen, Marc H.W.A., Vahrmeijer, Alexander L., Rios, Anne C., Hubrecht Institute with UMC, Wellens, Lianne M., Deken, Marion M., Sier, Cornelis F.M., Johnson, Hannah R., de la Jara Ortiz, Fàtima, Bhairosingh, Shadhvi S., Houvast, Ruben D., Kholosy, Waleed M., Baart, Victor M., Pieters, Annique M.M.J., de Krijger, Ronald R., Molenaar, Jan J., Wehrens, Ellen J., Dekkers, Johanna F., Wijnen, Marc H.W.A., Vahrmeijer, Alexander L., and Rios, Anne C.

Published
2020

188. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity

Author

Nefro Vasculaire Geneeskunde, Groep Holstege, CMM Groep Klumperman, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, Pathologie Groep Blokx, Pathologie Pathologen staf, Child Health, CMM Groep Cuppen, Cancer, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L., Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H.D., Visser, Lindy L., Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A.M., Kemmeren, Patrick, de Krijger, Ronald R., Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., van Boxtel, Ruben, Holstege, Frank C.P., Clevers, Hans, Drost, Jarno, Nefro Vasculaire Geneeskunde, Groep Holstege, CMM Groep Klumperman, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, Pathologie Groep Blokx, Pathologie Pathologen staf, Child Health, CMM Groep Cuppen, Cancer, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L., Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H.D., Visser, Lindy L., Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A.M., Kemmeren, Patrick, de Krijger, Ronald R., Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., van Boxtel, Ruben, Holstege, Frank C.P., Clevers, Hans, and Drost, Jarno

Published
2020

189. Neuroblastoma stage 4S: Tumor regression rate and risk factors of progressive disease

Author

Tas, Michelle L, Nagtegaal, Michelle, Kraal, Kathelijne C J M, Tytgat, Godelieve A M, Abeling, Nico G G M, Koster, Jan, Pluijm, Saskia M F, Zwaan, C Michel, de Keizer, Bart, Molenaar, Jan J, van Noesel, Max M, UU BETA RESEARCH, Pediatrics, Graduate School, ARD - Amsterdam Reproduction and Development, AGEM - Endocrinology, metabolism and nutrition, AGEM - Digestive immunity, CCA - Cancer Treatment and Quality of Life, Paediatric Oncology, Laboratory Genetic Metabolic Diseases, and UU BETA RESEARCH

Subjects
Male, Spontaneous/pathology, medicine.medical_specialty, Neuroblastoma/pathology, Gastroenterology, Cohort Studies, Excretion, Neuroblastoma, 03 medical and health sciences, Neoplasm Regression, Spontaneous/pathology, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Stage (cooking), Retrospective Studies, business.industry, Infant, Newborn, Infant, Retrospective cohort study, Hematology, Newborn, medicine.disease, Regression, Oncology, Neoplasm Regression, Spontaneous, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Cohort, Disease Progression, Stage 4S Neuroblastoma, Neoplasm Regression, Female, business, Progressive disease, 030215 immunology
Abstract

BACKGROUND: The clinical course of neuroblastoma stage 4S or MS is characterized by a high rate of spontaneous tumor regression and favorable outcome. However, the clinical course and rate of the regression are poorly understood. METHODS: A retrospective cohort study was performed, including all patients with stage 4S neuroblastoma without MYCN amplification, from two Dutch centers between 1972 and 2012. We investigated the clinical characteristics, the biochemical activity reflected in urinary catecholamine excretion, and radiological imaging to describe the kinetics of tumor regression, therapy response and outcome. RESULTS: The cohort of 31 patients reached a 10-year overall survival of 84% ± 7% (median follow-up 16 years; range, 3.3-39). During the regressive phase, liver size normalized in 91% of the patients and catecholamine excretion in 83%, both after a median of two months (liver size: range, 0-131; catecholamines: range, 0-158). The primary tumors completely regressed in 69% after 13 months (range, 6-73), and the liver architecture normalized in 52% after 15 months (range, 5-131). Antitumor treatment was given in 52% of the patients. Interestingly, regression rates were similar for treated and untreated patients. Four of seven patients < 4 weeks old died of rapid liver expansion and organ compression. Three patients progressed to stage 4, 3 to 13 months after diagnosis; all had persistently elevated catecholamines. CONCLUSION: Patients < 4 weeks old with neuroblastoma stage 4S are at risk of fatal outcome caused by progression of liver metastases. In other patients, tumor regression is characterized by a rapid biochemical normalization that precedes radiological regression.

Published
2019

190. Maami Waata's underwater kingdom; Perceptions of water in a changing hydrological and ecological context: the case of the logone flood plains in Cameroon

Author

Molenaar, Jan Willem and Van Santen, Jose C.M.

Subjects
Cameroon -- Environmental aspects, Cameroon -- Environmental policy, Environmental policy -- Interpretation and construction, Environmental policy -- Public opinion, Dams -- Design and construction, Dams -- Environmental aspects, Dams -- Government finance, Geography, World Bank -- Government finance
Abstract

We look at the beliefs of the population in North Cameroon concerning water, fish and water spirits in the context of the construction of a dam (1979) and of a flood embankment for a rice irrigation scheme financed by the World Bank. These operations caused a drought that had severe effects on the environment and the inhabitants' economic activities. Acknowledging the new approaches within development and ecological development thinking, we emphasize that local people are part of their environment, and that the environment and people's use of the ecosystem ought to be regarded as a functional unit. Our main argument is that the success of environmental strategies requires that the unequal power relations between the different actors and agencies and the perceptions of policymakers and NGOs be analysed and examined regularly in the course of a project to test their aims and integrity. In addition, the positions of beings and cosmological entities, which in the eyes of the population are 'actors of power to be reckoned with', like the water spirit, should also be included. The hidden agendas of all actors can be as difficult as the water spirit (Maama Waata) itself, by which we mean that hidden agendas are equally a part of reality as is the water spirit, even if they are not visible at first. KEYWORDS: Cameroon, perception, environment, development, power relations, water spirit

Published
2006

192. RRM2 is a target for synthetic lethal interactions with replication stress checkpoint addiction in high-risk neuroblastoma

Author

Nunes, Carolina, primary, Depestel, Lisa, additional, Mus, Liselot, additional, Keller, Kaylee, additional, Delhaye, Louis, additional, Louwagie, Amber, additional, Rishfi, Muhammad, additional, Dolman, Emmy, additional, Olexiouk, Volodimir, additional, Bartenhagen, Christoph, additional, De Vloed, Fanny, additional, Sanders, Ellen, additional, Eggermont, Aline, additional, Van Laere, Jolien, additional, Desmet, Els, additional, Van Loocke, Wouter, additional, Morscio, Julie, additional, Loontiens, Siebe, additional, Depuydt, Pauline, additional, Decaesteker, Bieke, additional, Tilleman, Laurentijn, additional, Van Nieuwerburgh, Filip, additional, Deforce, Dieter, additional, De Wilde, Bram, additional, Van Vlierberghe, Pieter, additional, Vermeirssen, Vanessa, additional, Goossens, Steven, additional, Eyckerman, Sven, additional, Van Neste, Christophe, additional, Roberts, Stephen, additional, Fischer, Matthias, additional, Molenaar, Jan, additional, Durinck, Kaat, additional, and Speleman, Frank, additional

Published
2020
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197. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Author

Poon, Evon, primary, Liang, Tong, additional, Jamin, Yann, additional, Walz, Susanne, additional, Kwok, Colin, additional, Hakkert, Anne, additional, Barker, Karen, additional, Urban, Zuzanna, additional, Thway, Khin, additional, Zeid, Rhamy, additional, Hallsworth, Albert, additional, Box, Gary, additional, Ebus, Marli E., additional, Licciardello, Marco P., additional, Sbirkov, Yordan, additional, Lazaro, Glori, additional, Calton, Elizabeth, additional, Costa, Barbara M., additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Webber, Hannah, additional, Tardif, Nicolas, additional, Almeida, Gilberto S., additional, Christova, Rossitza, additional, Boysen, Gunther, additional, Richards, Mark W., additional, Barone, Giuseppe, additional, Ford, Anthony, additional, Bayliss, Richard, additional, Clarke, Paul A., additional, De Bono, Johann, additional, Gray, Nathanael S., additional, Blagg, Julian, additional, Robinson, Simon P., additional, Eccles, Suzanne A., additional, Zheleva, Daniella, additional, Bradner, James E., additional, Molenaar, Jan, additional, Vivanco, Igor, additional, Eilers, Martin, additional, Workman, Paul, additional, Lin, Charles Y., additional, and Chesler, Louis, additional

Published
2020
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198. PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

Author

Milosevic, Jelena, primary, Fransson, Susanne, additional, Gulyas, Miklos, additional, Gallo-Oller, Gabriel, additional, Olsen, Thale K, additional, Treis, Diana, additional, Wickström, Malin, additional, Elfman, Lotta HM, additional, Sveinbjornsson, Baldur, additional, Hertwig, Falk, additional, Bartenhagen, Christoph, additional, Reinsbach, Susanne, additional, Wilhelm, Margareta, additional, Abel, Frida, additional, Javanmardi, Niloufar, additional, Thankaswamy-Kosalai, Subazini, additional, Eissler, Nina, additional, Kock, Anna, additional, Shi, Yao, additional, Tanino, Keiji, additional, Hehir-Kwa, Jane Y, additional, Mensenkamp, Arjen, additional, Tytgat, Godelieve AM, additional, Kanduri, Chandrasekhar, additional, Holmberg, Johan, additional, Gisselsson, David, additional, Molenaar, Jan J, additional, Jongmans, Marjolijn, additional, Fischer, Matthias, additional, Kool, Marcel, additional, Sakaguchi, Kazuyasu, additional, Baryawno, Ninib, additional, Martinsson, Tommy, additional, Johnsen, John Inge, additional, and Kogner, Per, additional

Published
2020
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199. Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

Author

George, Sally L, primary, Lorenzi, Federica, additional, King, David, additional, Hartlieb, Sabine, additional, Campbell, James, additional, Pemberton, Helen, additional, Toprak, Umut H, additional, Barker, Karen, additional, Tall, Jennifer, additional, da Costa, Barbara Martins, additional, van den Boogaard, Marlinde L, additional, Dolman, M Emmy M, additional, Molenaar, Jan J, additional, Bryant, Helen E, additional, Westermann, Frank, additional, Lord, Christopher J, additional, and Chesler, Louis, additional

Published
2020
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